Development of hypoxia-activated PROTAC exerting a more potent effect in tumor hypoxia than in normoxia.
Chem Commun (Camb)
; 57(95): 12852-12855, 2021 Nov 30.
Article
em En
| MEDLINE
| ID: mdl-34788776
ABSTRACT
Hypoxia is a hallmark of many solid tumors, and it causes the overexpression of a variety of proteins including the epidermal growth factor receptor (EGFR). Many antitumor prodrugs have been designed to target hypoxia. Here we report the identification of a kind of hypoxia-activated proteolysis targeting chimera (ha-PROTAC) by introducing the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4-nitrobenzyl into the structure of an EGFRDel19-based PROTAC. Among the obtained molecules, ha-PROTAC 13 exhibits a more potent degradation activity for EGFRDel19 in hypoxia than in normoxia in HCC4006 cells. This is the first example of identifying a PROTAC to selectively act on tumors utilizing the characteristic of tumor hypoxia and provides a new approach for PROTAC development.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Hipóxia Tumoral
/
Desenvolvimento de Medicamentos
/
Imidazóis
/
Nitrobenzenos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article